The objectives of this project are to delineate the cellular site(s) and mechanisms of action of the antimania drug lithium in mammalian brain, in an effort to understand what CNS deficits may underly the causes of affective psychosis. We have initiated our study of drug effects at the level of the cerebellar Purkinje cells in rats. 1) Iontophoretically administered lithium (Li) has an acute, direct, depressant effect on the spontaneous firing of these neurons. In these acute tests, Li occasionally antagonizes inhibitory responses of Purkinje cells to iontophoretic norepinephrine (NE) or to stimulation of the locus coeruleus, the source of NE fibers to Purkinje cells. Chronic Li treatment (by twice daily gavage sufficient to produce blood levels of 0.8-1.2 mEq) results in a significant reduction in Purkinje cell firing but with no attentuation of responses to iontophoretic NE. In order to provide a pharmacological comparison to these effects of Li, we also explored under similar experiments the effects of 10-14 day treatments with the tricyclic anti-depressant desmethylimipramine. 2) A single acute dose of DMI also slows Purkinje cell firing. Chronic orally administered DMI also slows Purkinje firing even more than Li but also significantly increases inhibitory thresholds to iontophoretic NE. Purkinje cell firing returns to normal with 5 days after cessation of either Li or DMI treatment, as do responses to iontophoretically applied NE after recovery from DMI.